| Domain | Finding | Evidence type | Source/date/DOI |
|---|---|---|---|
| 2024 phenotypic expansion | Three unrelated individuals had severe onset before 7 months with axial hypotonia, spastic quadriplegia, dystonia, seizures, and intellectual disability. Variants were de novo heterozygous p.(Lys406Glu), homozygous p.(Arg403Glufs*3), and homozygous p.(Tyr367His); asymptomatic heterozygous parents in the latter two families support rare autosomal-recessive SPG3A. (pqac-00000007, pqac-00000008) | Human case series | Hamamie-Chaar et al.; July 2024; [DOI: 10.1007/s00415-024-12565-0](https://doi.org/10.1007/s00415-024-12565-0) |
| Clinical frequency and penetrance | In Russia, SPG3A comprised 7.2% of 195 HSP families, 13.6% of 103 molecularly resolved families, and 16.9% of dominant forms. Among 14 SPG3A families, incomplete penetrance or subclinical disease occurred in five; 3 of 6 electrophysiologically tested patients had subclinical axonal polyneuropathy. (pqac-00000006) | Human cohort | Rudenskaya et al.; March 2020; [DOI: 10.25692/acen.2020.1.5](https://doi.org/10.25692/acen.2020.1.5) |
| Variant spectrum | In 122 Russian HSP probands, ATL1-related disease was found in 10 (8.2%), all familial. All ten variants were missense; most occurred in hotspot exons 4, 7, 8, and 12, and two were novel. (pqac-00000009) | Human molecular cohort | Kadnikova et al.; October 2019; [DOI: 10.1038/s41598-019-50911-9](https://doi.org/10.1038/s41598-019-50911-9) |
| Classic epidemiology and course | SPG3A represents approximately 10%–15% of dominant uncomplicated HSP and more than 75% of early-onset dominant cases. Typical onset is in the first decade—often age 1–3 years, with a reported mean of 4.6 years—and progression is generally slow with preserved ambulation; cerebral palsy is a recurrent initial misdiagnosis. (pqac-00000006, pqac-00000007, pqac-00000021) | Aggregated human clinical evidence | GeneReviews-derived overview; Rudenskaya et al. 2020; Hamamie-Chaar et al. 2024 |
| Causal gene and ER fusion | ATL1 encodes neuronally enriched atlastin-1, an ER-membrane dynamin-like GTPase. GTP-dependent dimerization, three-helix-bundle crossover, and amphipathic-helix insertion drive homotypic ER-membrane fusion; purified human ATL1 directly catalyzes GTP-dependent lipid mixing. The relative contributions of loss of function, dominant-negative action, and other mutation-specific effects remain unresolved. (pqac-00000011, pqac-00000012) | Biochemical, structural, and cellular evidence | Crosby et al.; November 2021; [DOI: 10.1083/jcb.202107070](https://doi.org/10.1083/jcb.202107070); Sonda et al.; October 2021; [DOI: 10.3390/cells10112870](https://doi.org/10.3390/cells10112870) |
| Astrocyte–neuron lipid mechanism | Isogenic ATL1-A161P and patient-derived ATL1-P342S models showed impaired axonal outgrowth and transport and axonal swellings. ATL1-mutant astrocytes had smaller lipid droplets and defective cholesterol transfer, causing neuronal cholesterol deficiency; cholesterol, control-conditioned medium, or the NR1H2/LXR agonist GW3965 rescued axonal abnormalities. (pqac-00000010) | Human hPSC/iPSC-derived cortical neurons and astrocytes; experimental rescue | Mou et al.; December 2020; [DOI: 10.1186/s40478-020-01088-0](https://doi.org/10.1186/s40478-020-01088-0) |
| Neuromuscular-junction model | Autologous iPSC-derived lower-motor-neuron and myotube cultures from three SPG3A and two SPG4 patients produced fewer, less-complex neuromuscular junctions; HSP neurons showed axonal swellings and acetylated α-tubulin accumulation. Findings are preclinical and were not separately quantified for SPG3A in the cited summary. (pqac-00000013) | Human patient-derived iPSC microfluidic model | Costamagna et al.; 24 October 2022; [DOI: 10.3390/cells11213351](https://doi.org/10.3390/cells11213351) |
| Current treatment | No therapy is proven to halt, reverse, or prevent SPG3A progression. Current HSP care is individualized and symptomatic: physiotherapy, stretching, orthoses, mobility aids, oral baclofen, tizanidine or dantrolene, focal botulinum toxin, intrathecal baclofen for severe refractory spasticity, and bladder-directed therapy such as oxybutynin. Evidence is predominantly general HSP evidence rather than SPG3A-specific trials. (pqac-00000017, pqac-00000018, pqac-00000022) | Systematic reviews and clinical-management evidence | Maccora et al.; online 16 November 2023 / 2024 issue; [DOI: 10.1007/s10072-023-07200-1](https://doi.org/10.1007/s10072-023-07200-1); Bellofatto et al.; 22 January 2019; [DOI: 10.3389/fneur.2019.00003](https://doi.org/10.3389/fneur.2019.00003) |


*Table: Highest-value clinical, genetic, mechanistic, model-system, and treatment evidence for ATL1-related hereditary spastic paraplegia 3A. The table distinguishes human observations from preclinical findings and flags the absence of disease-modifying therapy.*